ABSTRACT: Overall. The University of Iowa/Mayo Clinic Lymphoma SPORE (SPORE) is a dynamic, productive, translational cancer research program based at two comprehensive cancer centers that was first funded in 2002 and competitively renewed in 2007 and 2012. At the center of the ongoing success of the SPORE is the collaborative interaction between investigators at Iowa and Mayo, as well as SPORE basic laboratory, clinical and population science investigators focused on lymphoma. The overall goal of the SPORE is to support innovative, interactive, rigorous translational lymphoma research that leverages the expertise of laboratory, clinical and population science expertise at both institutions. Over the last funding period, the SPORE has been highly productive as demonstrated by identification of new tumor markers and prognostic indices that are being used clinically; scientific findings that led to innovative clinical trials both within and outside the SPORE; multiple publications with many authored by investigators from both institutions; and brisk accrual to translational clinical trials. The SPORE was involved in multiple productive vertical and horizontal collaborations with other national and international academic institutions and organizations. For example, the UI/MC Molecular Epidemiology Resource based in the SPORE is a vital resource for both SPORE research and research projects supported by other grants. It served as the foundation for the funding of the Lymphoma Epidemiology of Outcomes (LEO) Cohort (U01 CA195568) that includes 6 additional institutions, thereby enhancing the scope and diversity of research facilitated by the SPORE. The current proposal includes 4 major research projects. While all of the projects are new, they are based on research results obtained over the past funding period. Project 1 will investigate why the innate immune system (monocyte/macrophage) is suppressed in lymphoma and aims to overcome that suppression with a novel SIRP?-Fc in a phase I trial. Project 2 focuses on enhancing the clinical T-cell response by modifying the lymphoma microenvironment to augment antigen release, presentation of antigen, and T cell activation and combining it with anti-PD1 therapy of NHL. Project 3 is investigating the dysregulated signaling pathways (TRAF3 and GSK3) that regulate glucose hypermetabolism in aggressive lymphoma. They will test a novel GSK3 inhibitor in a phase I trial. Project 4 is a Population Science project will test a combination of germline (host) and somatic (tumor) genomic biomarkers, tumor gene expression, and clinical factors to predict at diagnosis which immunochemotherapy-treated FL patients will have an early clinical failure. The SPORE also includes Developmental Research and Career Enhancement Programs to pursue novel translational concepts in lymphoma research and new investigators through the programs respectively. Finally, the SPORE will enhance the infrastructure that supports translational lymphoma research at both institutions through shared core resources in Administration, Biostatistics and Bioinformatics, Biospecimens, and Clinical Research.